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LIM kinase 1-dependent cofilin 1 pathway and actin dynamics mediate nuclear retinoid receptor function in T lymphocytes

  1. Author:
    Ishaq, M.
    Lin, B. R.
    Bosche, M.
    Zheng, X.
    Yang, J.
    Huang, D. W.
    Lempicki, R. A.
    Natarajan, V.

  2. Author Address

    [Ishaq, M; Lin, BR; Natarajan, V] NCI, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA. [Bosche, M; Zheng, X; Yang, J; Huang, DW; Lempicki, RA] NCI, Lab Immunopathogenesis & Bioinformat, SAIC Frederick, Frederick, MD 21702 USA.;Ishaq, M (reprint author), NCI, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA;mishaq@mail.nih.gov
    1. Year: 2011
    2. Date: Sep
  2. Journal: Bmc Molecular Biology
    1. 12
    2. Pages: 14
  4. Type of Article: Article
  5. Article Number: 41
  6. ISSN: 1471-2199
  1. Abstract:

    Background: It is known that retinoid receptor function is attenuated during T cell activation, a phenomenon that involves actin remodeling, suggesting that actin modification may play a role in such inhibition. Here we have investigated the role of actin dynamics and the effect of actin cytoskeleton modifying agents on retinoid receptor-mediated transactivation. Results: Agents that disturb the F-actin assembly or disassembly attenuated receptor-mediated transcription indicating that actin cytoskeletal homeostasis is important for retinoid receptor function. Overexpression or siRNA-induced knockdown of cofilin-1 (CFL1), a key regulator of F-actin assembly, induced the loss of receptor function. In addition, expression of either constitutively active or inactive/dominant-negative mutants of CFL1or CFL1 kinase LIMK1 induced loss of receptor function suggesting a critical role of the LIMK1-mediated CFL1 pathway in receptor-dependent transcription. Further evidence of the role of LMK1/CFL1-mediated actin dynamics, was provided by studying the effect of Nef, an actin modifying HIV-1 protein, on receptor function. Expression of Nef induced phosphorylation of CFL1 at serine 3 and LIMK1 at threonine 508, inhibited retinoid-receptor mediated reporter activity, and the expression of a number of genes that contain retinoid receptor binding sites in their promoters. The results suggest that the Nef-mediated inhibition of receptor function encompasses deregulation of actin filament dynamics by LIMK1 activation and phosphorylation of CFL1. Conclusion: We have identified a critical role of LIMK1-mediated CFL1 pathway and actin dynamics in modulating retinoid receptor mediated function and shown that LIMK1-mediated phosphocycling of CFL1 plays a crucial role in maintaining actin homeostasis and receptor activity. We suggest that T cell activation-induced repression of nuclear receptor-dependent transactivation is in part through the modification of actin dynamics.

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External Sources

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  2. DOI: 10.1186/1471-2199-12-41
  3. View record in Web of Science®
  4. WOS: 000295783600001

Library Notes

  1. Fiscal Year: FY2011-2012
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